A 5-year-old boy is undergoing a complete physical exam prior to starting kindergarten and the pediatrician notes some papules over the right Achilles tendon (Figure 193-1A). She also notes rings around the peripheral corneas of both eyes that could be arcus juvenilis (Figure 193-1B). The mom noticed the papules near the foot about 2 months ago but had not noticed anything unusual about the eyes. The pediatrician suspects that these findings could be secondary to elevated lipids and discovers that the mother has type 2 diabetes along with high cholesterol. The child is sent for a fasting lipid panel and blood sugar. The results confirm familial hypercholesterolemia (total cholesterol of 810 mg/dL and a low density lipoprotein of 507 mg/dL). The papules over the Achilles tendon are tendinous xanthomas and the eyes do show arcus juvenilis secondary to the elevated lipids. The child is referred to endocrinologist and the mother is told that all the family should be tested and everyone should be eating a low fat diet.

Hyperlipidemia refers to an elevated concentration of one or more of the measured serum lipid components (total cholesterol [TC], low-density lipid [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]). Xanthomas are a skin manifestation of familial or severe secondary hyperlipidemia, although they can occur in patients with normal lipid levels. Hyperlipidemia is a major modifiable risk factor for cardiovascular disease.

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  Among young adults, ages 12 to 19 years, 20.3 percent have abnormal lipids; boys are more likely than girls to have at least 1 lipid abnormality (24.3% versus 15.9%, respectively).¹

  
  
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  Patients with homozygous familial hypercholesterolemia (FH) (1 in 1 million persons worldwide) present in childhood with cutaneous xanthomas on the hands, wrists, elbows, knees, heels, or buttocks.²

  
  
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  In one population study, children of parents with coronary artery disease were more likely to be overweight and have dyslipidemia in childhood.³

  
  
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  Large epidemiological studies indicate that children’s lipid levels correlate with their adult family members levels.⁴

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  Causes of primary lipid disorders most common seen in children and adolescents are familial combined hyperlipidemia and FH (heterozygous; Figure 193-1). Secondary causes include obesity, metabolic syndrome, hypothyroidism, hypopituitarism, diabetes mellitus (type 1 and type 2), polycystic ovary syndrome, juvenile rheumatoid arthritis, chronic renal disease including nephrotic syndrome, Kawasaki disease, and hepatitis.

  
  
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  Lipoproteins are complexes of lipids and proteins essential for transporting cholesterol, TGs, and fat-soluble vitamins.

  
  
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  Elevated levels can result from genetically based derangement of lipid metabolism and/or transport or from secondary causes (listed above), cigarette smoking, obesity, or drugs (e.g., corticosteroids, estrogens, retinoids, and high-dose β-blockers).

  
  
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  Increased circulating LDL becomes incorporation into atherosclerotic plaques. These plaques can grow to block blood supply and oxygen delivery resulting in ischemia to vital organs. In addition, if the plaque ruptures, it can precipitate a clot, causing for example myocardial infarction.

  
  
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  Elevated TG is an independent risk factor for CHD and increases the risk of hepatomegaly, splenomegaly, hepatic steatosis, and pancreatitis. Contributing factors include obesity, physical inactivity, cigarette smoking, excess alcohol intake, medical diseases (e.g., type 2 DM, chronic renal failure, nephrotic syndrome), drugs (as previously discussed), and genetic disorders (e.g., familial combined hyperlipidemia).⁵

  
  
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  Autopsy studies show a correlation between lipid levels and arterial fat disposition in young adults and children.^6,7

  
  
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  Xanthomas are deposits of lipid in the skin or subcutaneous tissue, usually occurring as a consequence of primary or secondary hyperlipidemia. Xanthomas can also be seen in association with monoclonal gammopathy.⁸ There are five basic types of xanthomas:

  
  
  
  
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    Eruptive xanthomas (also called tuberoeruptive) are the most common form. These appear as crops of yellow or hyperpigmented papules with erythematous halos in white persons (Figure 193-2), appearing hyperpigmented in black persons.

    
    
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    Tendon xanthomas are frequently seen on the Achilles (Figure 193-1) and extensor finger tendons.

    
    
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    Plane xanthomas are flat and commonly seen on the palmar creases, face, upper trunk, and on scars.

    
    
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    Tuberous xanthomas are found most frequently on the hand or over large joints.

    
    
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    Xanthelasma are yellow papules found on the eyelids (Figure 193-3). Fifty percent of individuals with xanthelasmas have normal lipid profiles.

Risk factors and high-risk conditions to consider for treatment decisions in children with hyperlipidemia include:⁹

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  Positive family history of myocardial infarction; angina; coronary artery bypass graft/stent/angioplasty; sudden cardiac death in parent, grandparent, aunt, or uncle (if male at age <55 years and female at age <65 years).

  
  
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  High-level risk factors including hypertension requiring drug therapy, BMI ≥97^th percentile, and current cigarette smoker.

  
  
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  Moderate level risk factors including hypertension not requiring drug therapy, BMI ≥95^th but <97^th percentile, and HDL-C <40 mg/dL.

  
  
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  The presence of high risk conditions including diabetes mellitus, chronic kidney disease/end-stage renal disease/post renal transplant, post orthotopic heart transplant, and Kawasaki disease with current aneurysms.

  
  
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  The presence of moderate risk conditions including Kawasaki disease with regressed coronary aneurysms, chronic inflammatory disease (e.g., systemic lupus erythematosus, juvenile rheumatoid arthritis), nephrotic syndrome, and human immunodeficiency virus infection.

Clinical Features

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  Most patients with hyperlipidemia are asymptomatic.

  
  
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  A very high TC level (>2000 mg/dL) can result in eruptive xanthomas or lipemia retinalis (white appearance of the retina; also seen with isolated high TG). Very high LDL can lead to the formation of tendinous xanthomas.

  
  
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  Xanthomas manifest clinically as yellowish papules, nodules, or tumors (Figure 193-1).

  
  
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  Eruptive xanthomas (Figures 193-4 to 193-5) begin as clusters of small papules on the elbows, knees, and buttocks that can grow to the size of grapes.

Typical Distribution

Xanthomas are most commonly found in superficial soft tissues, such as skin and subcutis, or on tendon sheaths.

Laboratory Testing

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  Acceptable, borderline, and high values for plasma lipid and lipoprotein levels based on the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children are shown in Table 193-1.¹⁰ The cut points for high and borderline represent approximately the 95^th and 75^th percentiles, respectively.^11,12 Low cut points for HDL-C represent approximately the 10^th percentile.¹³

  
  
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  If thyroid dysfunction is suspected, obtain a thyroid-stimulating hormone level to determine whether thyroid dysfunction is contributing to the lipid abnormalities.